The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1

被引:83
作者
Qin, Liuliang [1 ]
Zhao, Dezheng [2 ,3 ]
Xu, Jianfeng [4 ]
Ren, Xianghui [4 ]
Terwilliger, Ernest F. [4 ]
Parangi, Sareh [5 ]
Lawler, Jack [1 ,3 ]
Dvorak, Harold F. [1 ,3 ]
Zeng, Huiyan [3 ,6 ]
机构
[1] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA
[2] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02215 USA
[3] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Vasc Biol Res Ctr, Boston, MA 02215 USA
[4] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Expt Med,Dept Med, Boston, MA 02215 USA
[5] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA
[6] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Mol & Vasc Biol,Dept Med, Boston, MA 02215 USA
基金
美国国家卫生研究院;
关键词
NITRIC-OXIDE SYNTHASE; MAST-CELL HISTAMINE; GROWTH-FACTOR; VEGF-A; RECEPTOR; CANCER; TISSUE; PROLIFERATION; INFLAMMATION; EXPRESSION;
D O I
10.1182/blood-2012-07-443903
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Angiogenesis plays an important role in cancer and in many other human diseases. Vascular endothelial growth factor-A (VEGF-A), the best known angiogenic factor, was originally discovered as a potent vascular permeability factor (VPF), suggesting that other vascular permeabilizing agents, such as histamine and serotonin, might also have angiogenic activity. We recently demonstrated that, like VEGF-A, histamine and serotonin up-regulate the orphan nuclear receptor and transcription factor TR3 (mouse homolog Nur77) and that TR3/Nur77 is essential for their vascular permeabilizing activities. We now report that histamine and serotonin are also angiogenic factors that, at low micromolar concentrations, induce endothelial cell proliferation, migration and tube formation in vitro, and angiogenesis in vivo. All of these responses are mediated through specific histamine and serotonin receptors, are independent of VEGF-A, and are directly dependent on TR3/Nur77. Initially, the angiogenic response closely resembled that induced by VEGF-A, with generation of "mother" vessels. However, after similar to 10 days, mother vessels began to regress as histamine and serotonin, unlike VEGF-A, up-regulated the potent angiogenesis inhibitor thrombospondin-1, thereby triggering a negative feedback loop. Thus, histamine and serotonin induce an angiogenic response that fits the time scale of acute inflammation.
引用
收藏
页码:2154 / 2164
页数:11
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